Complete understanding of the regulation of bone resorption by hormones and drugs could provide a rational basis for the treatment of metabolic bone diseases involving increased bone resorption (e.g. osteoporosis and Paget's disease) and of inflammatory bone lysis (e.g. periodontal disease and rheumatoid arthritis). Such information would also be useful for the problem of unpredictable bone graft resorption. New experimental models are needed to demonstrate the origin, differentiation, and regulation of bone resorbing cells. We have developed a model for osteoclastic bone resorption. The subcutaneous implantation of mineral-containing, devitalized bone particles (BP) in rats induces the appearance of multinucleated cells that have many features of in osso osteoclasts. These cells can be distinguished from foreign body giant cells elicited by particulate polymethylmethacrylate because only the former express tartrate-resistant acid phosphatase activity, calcitonin receptors, and ruffled borders overlying the bone substrate being resorbed. Using these models, we propose to investigate various aspects of the biology of the osteoclast: its differentiation, mechanisms of bone resorption, and regulation by bone-active agents. The specific aims are to characterize the process of differentiation of osteoclasts induced by bone particles, to determine the role of mast cells and lymphocytes and the effect of non-steroidal anti-inflammatory agents in their differentiation and activity, and to elucidate the mechanism of PTH's effects on resorption. The methods to be used include histomorphometrics, electron microscopy, immunocytochemistry, cell culture, evaluation of calcitonin receptors, and biochemical assessment of tartrate-resistant acid phosphatase activity. By evaluating the sequence of differentiation of these osteoclasts and foreign body giant cells, we will test the hypothesis that they have separate progenitor cells. Furthermore, the mechanism of the effects of parathyroid hormone and of non-steroidal anti-inflammatory cells on differentiation and cellular activity will be determined.